Intratympanic dexamethasone microcrystals/lidocaine-loaded PLGA non-spherical microparticles for local drug delivery to the inner ear

Abstract

Background: Sudden sensorineural hearing loss (SSNHL), often associated with tinnitus, significantly impacts individuals' quality of life. Current treatments, such as free drugs via intravenous or intratympanic (IT) administration of dexamethasone (DEX) and lidocaine, face limitations like low bioavailability and rapid drug clearance. To address these challenges, we developed a local co-delivery system combining DEX microcrystals (DEX MCs) and lidocaine-loaded poly(lactic-co-glycolic acid) (PLGA) non-spherical microparticles (LPNMs) for sustained drug release in the inner ear.

Methods: DEX MCs and LPNMs were prepared using the traditional precipitation technique and double emulsion-solvent evaporation, respectively. After characterizing physicochemical properties and drug release kinetics, they were dispersed in sodium hyaluronate solution for IT injection, then in vivo pharmacokinetics and biocompatibility in guinea pigs were studied.

Results: DEX MCs exhibited stable dissolution, while LPNMs provided sustained lidocaine release, reducing potential side effects. In vivo studies in guinea pigs demonstrated prolonged drug retention in the perilymph and improved pharmacokinetics. Histological evaluation confirmed the good biocompatibility of this combined delivery system, with no significant inner ear damage observed.

Conclusion: This co-delivery system can be used as a depot for delivering both DEX and lidocaine to the inner ear and offers a promising approach for the synergistic treatment of SSNHL associated with tinnitus.

Keywords

dexamethasone / inner ear delivery / lidocaine / microcrystals / non-spherical particles

References

[1] Schreiber BE, Agrup C, Haskard DO, Luxon LM. Sudden sensorineural hearing loss. Lancet. 2010;375:1203-1211.

[2] Li M, Ai M, Yang Y, et al. Silk-coated dexamethasone non-spherical microcrystals for local drug delivery to inner ear. Eur J Pharm Sci. 2020;150:105336.

[3] Chandrasekhar SS. Intratympanic dexamethasone for sudden sensorineural hearing loss: clinical and laboratory evaluation. Otol Neurotol. 2001;22:18-23.

[4] Hoda E, Ayat A, Ewida M, Amal H. Intratympanic dexamethasone injection in chronic tinnitus associated with SNHL. Med J Cairo Univ. 2018;86:2909-2916.

[5] Yoshida T, Teranishi M, Iwata T, Otake H, Nakashima T. Intratympanic injection of dexamethasone for treatment of tinnitus in patients with sudden sensorineural hearing loss. Audiol Res. 2012;2:e2.

[6] Weshahy HF, Mohamed ES, Salem MAM, Hussein MMM. Intratympanic injection of dexamethasone for controlling subjective idiopathic tinnitus. Egypt J Otolaryngol. 2015;31:224-230.

[7] Baguley D, McFerran D, Hall D. Tinnitus. Lancet. 2013;382:1600-1607.

[8] Melding PS, Goodey RJ, Thorne PR. The use of intravenous lignocaine in the diagnosis and treatment of tinnitus. J Laryngol Otol. 1978;92:115-121.

[9] Podoshin L, Fradis M, David YB. Treatment of tinnitus by intratympanic instillation of lignocaine (lidocaine) 2 per cent through ventilation tubes. J Laryngol Otol. 1992;106:603-606.

[10] Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg. 2006;102:263-267.

[11] Elzayat S, El-Sherif H, Hegazy H, Gabr T, El-Tahan A-R. Tinnitus: evaluation of Intratympanic injection of combined lidocaine and corticosteroids. ORL. 2016;78:159-166.

[12] Elzayat S, Ragab S, Eisa M, Amer M, Mandour MF, Mehraz M. Evaluation of adding lidocaine to dexamethasone in the intra-tympanic injection for Management of Tinnitus: a prospective, randomized, controlled double-blinded trial. Int Tinnitus J. 2018;22:54-59.

[13] Hao J, Li SK. Inner ear drug delivery: recent advances, challenges, and perspective. Eur J Pharm Sci. 2019;126:82-92.

[14] Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of therapeutics to the inner ear: the challenge of the blood-labyrinth barrier. Sci Transl Med. 2019;11:eaao0935.

[15] Xiong H, Zhang P, Wang D, Zhou Z, Sun J, Diao M. A silk-based hydrogel containing dexamethasone and lipoic acid microcrystals for local delivery to the inner ear. Colloids Surf B Biointerfaces. 2024;237:113855.

[16] Mäder K, Lehner E, Liebau A, Plontke SK. Controlled drug release to the inner ear: concepts, materials, mechanisms, and performance. Hear Res. 2018;368:49-66.

[17] Horie RT, Sakamoto T, Nakagawa T, et al. Sustained delivery of lidocaine into the cochlea using poly lactic/glycolic acid microparticles. Laryngoscope. 2010;120:377-383.

[18] Yi X, Guo L, Zeng Q, et al. Magnetic/acoustic dual-controlled microrobot overcoming Oto-biological barrier for on-demand multidrug delivery against hearing loss. Small. 2024;20:2401369.

[19] Xu K, Du Y, Xu B, et al. Gelatin-encapsulated tetrahedral DNA nanostructure enhances cellular internalization for treating noise-induced hearing loss. Small. 2024;20:2310604.

[20] Champion JA, Mitragotri S. Role of target geometry in phagocytosis. Proc Natl Acad Sci. 2006;103:4930-4934.

[21] Zhang J, Wang J, Qiao F, et al. Polymeric non-spherical coarse microparticles fabricated by double emulsion-solvent evaporation for simvastatin delivery. Colloids Surf B Biointerfaces. 2021;199:111560.

[22] Zhou Z, Anselmo AC, Mitragotri S. Synthesis of protein-based, rod-shaped particles from spherical templates using layer-by-layer assembly. Adv Mater. 2013;25:2723-2727.

[23] Zhou Z, Xu J, Liu X, et al. Non-spherical racemic polylactide microarchitectures formation via solvent evaporation method. Polymer. 2009;50:3841-3850.

[24] Li R, Li X, Liu L, Zhou Z, Tang H, Zhang Q. High-yield fabrication of PLGA non-spherical microarchitectures by emulsion-solvent evaporation method. Macromol Rapid Commun. 2010;31:1981-1986.

[25] Liao L, Liu J, Dreaden EC, et al. A convergent synthetic platform for single-nanoparticle combination cancer therapy: Ratiometric loading and controlled release of cisplatin, doxorubicin, and Camptothecin. J Am Chem Soc. 2014;136:5896-5899.

[26] Wang X, Xiong H, Zhang P, et al. Intratympanic microcrystals of dexamethasone and lipoic acid for the treatment of cisplatin-induced inner ear injury. Colloids Surf B Biointerfaces. 2023;223:113191.

[27] Gao C, Yuan W, Wang D, Zhang X, Zhang T, Zhou Z. Adipose-derived mesenchymal stem cell-incorporated PLLA porous microspheres for cartilage regeneration. Anim Models Exp Med. 2024;7:685-695.

[28] Gouveris H, Selivanova O, Mann W. Intratympanic dexamethasone with hyaluronic acid in the treatment of idiopathic sudden sensorineural hearing loss after failure of intravenous steroid and vasoactive therapy. Eur Arch Otorhinolaryngol. 2005;262:131-134.

[29] Ng S-M, Choi J-Y, Han H-S, Huh J-S, Lim JO. Novel microencapsulation of potential drugs with low molecular weight and high hydrophilicity: hydrogen peroxide as a candidate compound. Int J Pharm. 2010;384:120-127.

[30] Mandal TK, Tenjarla S. Preparation of biodegradable microcapsules of zidovudine using solvent evaporation: effect of the modification of aqueous phase. Int J Pharm. 1996;137:187-197.

[31] Nafisi S, Samadi N, Houshiar M, Maibach HI. Mesoporous silica nanoparticles for enhanced lidocaine skin delivery. Int J Pharm. 2018;550:325-332.

[32] Ai M, Guo C, Wang L, et al. Modulating surface charge of dexamethasone non-spherical microcrystals for improved inner ear delivery. Colloids Surf B Biointerfaces. 2021;204:111806.

[33] García-Abuín A, Gómez-Díaz D, Navaza JM, Regueiro L, Vidal-Tato I. Viscosimetric behaviour of hyaluronic acid in different aqueous solutions. Carbohydr Polym. 2011;85:500-505.

[34] Mueller-Goymann CC, Frank SG. Interaction of lidocaine and lidocaine-HCl with the liquid crystal structure of topical preparations. Int J Pharm. 1986;29:147-159.

[35] Chokshi RJ, Shah NH, Sandhu HK, Malick AW, Zia H. Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration. J Pharm Sci. 2008;97:2286-2298.

[36] Yoo J-W, Mitragotri S. Polymer particles that switch shape in response to a stimulus. Proc Natl Acad Sci. 2010;107:11205-11210.

[37] Atturo F, Barbara M, Rask-Andersen H. Is the human round window really round? An anatomic study with surgical implications. Otol Neurotol. 2014;35:1354-1360.

[38] Ghiz AF, Salt AN, DeMott JE, Henson MM, Henson OW, Gewalt SL. Quantitative anatomy of the round window and cochlear aqueduct in Guinea pigs. Hear Res. 2001;162:105-112.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.